The prime objective of this proposal is to produce a large animal model of macular degeneration using the gene ELOVL4. Transgenic pigs may be useful for the elucidation of the molecular mechanisms responsible for macular degeneration and for the development of therapeutic interventions. The pig's similarity to humans in size and retinal anatomy and physiology make it a logical choice for these experiments. Further, the production of transgenic pigs is a virtual surety. Only transgenic primates would provide a more accurate model, however, both the low supply of primates and low efficiency of these procedures will likely prevent gone transfer being a routine procedure in primates. Using a positional cloning approach, one of us (Zhang) has identified a disease gene called ELOVL4, which is responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3) and autosomal dominant macular dystrophy (adMD). STGD3 and adMD are two related forms of inherited macular degeneration characterized by decreased visual acuity, macular atrophy, and fundus flecks. A single five base-pair deletion in the coding region of ELOVL4 is found in all affected members of four independent STGD3 families and one adMD family. The deletion generates a frame-shift mutation and results in loss of 51 amino acids at the C-terminus including a putative di-lysine ER targeting signal. ELOVL4 demonstrated cone and rod photoreceptor specific expression in the eye and encoded a putative transmembrane protein with similarities to the ELO family of proteins involved in elongation of very long chain fatty acids. Stargardt's macular dystrophy is the most common juvenile macular degeneration and shares many important clinical and histopathological similarities with AMD including an abnormal accumulation of lipofuscin in the RPE, atrophy of the RPE and overlying photoreceptor cells, and loss of central vision. ELOVL4 is the first gene involved in the biosynthesis of long chain fatty acids implicated in any form of photoreceptor degeneration. Studies of pigs transgenic for ELOVL4 should lead to new insights into lipid metabolism in photoreceptor cells and may reveal a novel pathway in the pathogenesis of macular degeneration.